Department: Department of Pharmacology and Toxicology

Phone: (804) 828 6995

Email: said.sebti@vcuhealth.org

Address/Location:
Massey Cancer Center 401 College Street Goodwin Research Laboratories, Room 325

Professor / Department of Pharmacology and Toxicology

Associate Director for Basic Research / Massey Cancer Center

Address/Location: Massey Cancer Center 401 College Street Goodwin Research Laboratories, Room 325 Richmond, Virginia, 23298

Education

· B.S. Washington State University, 1980

· Ph.D. Purdue University, 1984

Research interests

The Sebti laboratory is focused on the mechanisms by which normal cells become cancerous with an emphasis on aberrant signal transduction pathways. Broadly the research areas of interests are related to signal transduction pathways from receptor tyrosine kinases to transcription factors. A major focus is on pathways regulated by the Ras family of GTPases. The work involves mechanistic studies of oncogenesis at the basic science level, validating cancer-causing proteins and pathways, developing chemical probes to target such pathways, and ultimately performing biomarker-driven clinical trials. Among our accomplishments are the discovery and development of inhibitors of aberrant signal transduction pathways such as inhibitors of STAT3, farnesyltransferase (FT), geranylgeranyltransferase-1 (GGT-1), Akt, RhoKinase, AuroraKinase, Proteasome, Bcl/Bax, Raf-1/Rb, Shp2, MDM2/p53 and others. Some of our findings including those with inhibitors of GGT-1 and Akt that have been translated from the laboratory to the clinic.

Currently, we are funded by a National Cancer Institute R35 Outstanding Investigator Award focusing on understanding the mechanism by which mutant KRas causes cancer. This is an exciting and highly integrated inter-disciplinary research projects concerning understanding aberrant oncogenic KRas signal transduction pathways in cancer and designing novel anti-cancer drugs based on this knowledge, with the following projects: 

• Understanding how oncogenic K-Ras and Ral GTPase regulate the tumor suppressor p53.

• Identifying kinases that are synthetically lethal with mutant K-Ras.

• Identifying small molecules that bind K-Ras and inhibit its GTP activation, binding to its effectors and blocking oncogenesis.

• Identifying cell surface proteins specifically expressed on human cancers that harbor mutant K-Ras.

• Developing dual FT and GGT-1 inhibitors as novel anti-cancer drugs targeting human tumors that harbor mutant K-Ras. 

Selected publications

Kazi A, Xiang S, Yang H, Delitto D, Trevino J, Jiang H, Ayaz M, Lawrence H, Kennedy, P and Sebti SM. GSK3 Suppression Upregulates β-Catenin and c-Myc to Abrogate KRas-Dependent Tumors. Nature Communications. 2018 Dec 4; 9:5154.

Kazi A, Zhang X, Luo Y, Patel R, Fletcher S, Cummings C, Lawrence H, Hamilton AD, and Sebti SM. Dual Farnesyl and Geranylgeranyl Transferase Inhibitor Thwarts Mutant KRas-Driven Patient-Derived Pancreatic Tumors. Clinical Cancer Research (In press).

Karasic TB, Chiorean EG, Sebti SM, O’Dwyer PJ. A Phase I Study of GGTI-2418 (Geranylgeranyl Transferase I Inhibitor) in Patients with Advanced Solid Tumors Cancer. Targeted Oncology (In Press).

Kuchay S, Giorgi C, Simoneschi D, Pagan J, Missiroli S, Saraf A, Florens L, Washburn MP, Collazo-Lorduy A, Castillo-Martin M, Cordon-Cardo C, Sebti SM, Pinton P, Pagano M. PTEN counteracts FBXL2 to promote IP3R3- and Ca(2+)-mediated Apoptosis limiting tumour growth. Nature. 2017 Jun 22;546(7659):554-558.

Tecleab A, Zhang X, Sebti SM. Ral GTPase down regulation stabilizes and reactivates p53 to inhibit malignant transformation. J Biol Chem. 2014 Nov 7;289(45):31296-309

Berndt N, Hamilton AD and Sebti SM. Targeting protein prenylation for cancer therapy. Nat Rev Cancer. 2011; 11(11): 775-91

Sebti, SM. Protein farnesylation: implications for normal physiology, malignant transformation, and cancer therapy. Cancer Cell. 2005 Apr; 7(4): 297-300.

Adnane J, Jackson RJ, Nicosia SV, Cantor AB, Pledger WJ, Sebti SM. Loss of p21WAF1/CIP1 accelerates Ras oncogenesis in a transgenic/knockout mammary cancer model. Oncogene. 2000 Nov 9;19(47):5338-47.

Jiang K, Sun J, Cheng J, Djeu JY, Wei S and Sebti S. Akt mediates Ras downregulation of RhoB, a suppressor of transformation, invasion, and metastasis. Mol Cell Biol. 2004 Jun; 24(12): 5565-76. 

Lerner EC, Qian Y, Blaskovich MA, Fossum RD, Vogt A, Sun J, Cox AD, Der CJ, Hamilton AD and Sebti SM. Ras CAAX peptidomimetic FTI-277 selectively blocks oncogenic Ras signaling by inducing cytoplasmic accumulation of inactive Ras-Raf complexes. J Biol Chem. 1995 Nov 10; 270(45): 26802-6.

Sun J, Qian Y, Hamilton AD, and Sebti SM. Ras CAAX peptidomimetic FTI 276 selectively blocks tumor growth in nude mice of a human lung carcinoma with K-Ras mutation and p53 deletion. Cancer Res. 1995 Oct 1; 55(19): 4243-7. 

Crespo NC, Delarue F, Ohkanda J, Carrico D, Hamilton AD, Sebti SM. The farnesyltransferase inhibitor, FTI-2153, inhibits bipolar spindle formation during mitosis independently of transformation and Ras and p53 mutation status. Cell Death Differ. 2002 Jul; 9(7): 702-9.

Lerner EC, Zhang TT, Knowles DB, Qian Y, Hamilton AD and Sebti SM. Inhibition of the prenylation of K-Ras, but not H- or N-Ras, is highly resistant to CAAX peptidomimetics and requires both a farnesyltransferase and a geranylgeranyltransferase I inhibitor in human tumor cell lines. Oncogene. 1997 Sep; 15(11): 1283-8.

Falsetti SC, Wang DA, Peng H, Carrico D, Cox AD, Der CJ, Hamilton AD, Sebti SM. Geranylgeranyltransferase I inhibitors target RalB to inhibit anchorage-dependent growth and induce apoptosis and RalA to inhibit anchorage-independent growth. Mol Cell Biol. 2007 Nov; 27(22): 8003-14.

Kazi A, Carie A, Blaskovich MA, Bucher C, Thai V, Moulder S, Peng H, Carrico D, Pusateri E, Pledger WJ, Berndt N, Hamilton A, Sebti SM. Blockade of protein geranylgeranylation inhibits Cdk2-dependent p27Kip1 phosphorylation on Thr187 and accumulates p27Kip1 in the nucleus: implications for breast cancer therapy. Mol Cell Biol. 2009 Apr; 29(8): 2254-63.

Zhang X, Sun Y, Pireddu R, Yang H, Urlam MK, Lawrence HR, Guida WC, Lawrence NJ and Sebti SM. A Novel Inhibitor of STAT3 Homodimerization Selectively Suppresses STAT3 Activity and Malignant Transformation. Cancer Res. 2013;73(6):1922-33.

Berndt N, Yang H, Trinczek B, Betzi S, Zhang Z, Wu B, Lawrence NJ, Pellecchia M, Schönbrunn E, Cheng JQ and Sebti SM. The Akt activation inhibitor TCN-P inhibits Akt phosphorylation by binding to the PH domain of Akt and blocking its recruitment to the plasma membrane. Cell Death Differ. 2010 Nov; 17(11): 1795-804.

Patel RA, Forinash KD, Pireddu R, Sun Y, Sun N, Martin MP, Schönbrunn E, Lawrence NJ and Sebti SM. RKI-1447 is a potent inhibitor of the Rho-associated ROCK kinases with anti-invasive and anti-tumor activities in breast cancer. Cancer Res. 2012; 72:5025-5034.

Complete list of Sebti published work can be found in the following URL: https://www.ncbi.nlm.nih.gov/sites/myncbi/said.sebti.1/bibliography/41161645/public/?sort=date&direction=ascending

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